3' UTR lengthening as a novel mechanism in regulating cellular senescence.
3' UTR lengthening as a novel mechanism in regulating cellular senescence.
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DOI：
10.1101/gr.224451.117
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发表时间：
2018-03-01
期刊：
影响因子：
7
通讯作者：
Ni T
中科院分区：
文献类型：
--
作者：
Chen M;Lyu G;Han M;Nie H;Shen T;Chen W;Niu Y;Song Y;Li X;Li H;Chen X;Wang Z;Xia Z;Li W;Tian XL;Ding C;Gu J;Zheng Y;Liu X;Hu J;Wei G;Tao W;Ni T
细胞衰老被认为是一种肿瘤抑制机制，也是个体衰老的一个因素。近年来，在癌细胞中发现了信使RNA（mRNA）3′非翻译区（3′ UTR）的交替多聚腺苷酸化（阿帕）缩短。然而，阿帕在细胞衰老过程中的作用仍然难以捉摸。在这里，我们发现衰老细胞中的数百个基因倾向于使用远端poly（A）（pA）位点，导致3′ UTR的整体延长和基因表达减少。在衰老细胞中具有较长3′ UTR的基因在衰老相关途径中富集。Ras超家族成员Rras2参与多种信号转导途径，其3′ UTR的使用时间较长，在衰老细胞中表达减少。Rras 2的耗竭促进衰老，而Rras 2的拯救逆转衰老相关的表型。机制上，剪接因子TRA2B结合到位于Rras 2的替代3′ UTR的核心“AGAA”基序，从而降低RRAS 2蛋白水平并引起衰老。近端和远端的poly（A）信号都显示出很强的序列保守性，突出了阿帕调节在进化过程中的重要作用。我们的研究结果揭示了阿帕作为一种新的机制，在调节细胞衰老。
Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3′ untranslated regions (3′ UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3′ UTRs and reduced gene expression. Genes that harbor longer 3′ UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3′ UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes. Mechanistically, splicing factor TRA2B bound to a core “AGAA” motif located in the alternative 3′ UTR of Rras2, thereby reducing the RRAS2 protein level and causing senescence. Both proximal and distal poly(A) signals showed strong sequence conservation, highlighting the vital role of APA regulation during evolution. Our results revealed APA as a novel mechanism in regulating cellular senescence.
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影响因子：
4.5
作者：
Hoffman Y;Bublik DR;Ugalde AP;Elkon R;Biniashvili T;Agami R;Oren M;Pilpel Y
通讯作者：
Pilpel Y
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
12.3
作者：
Elkon R;Drost J;van Haaften G;Jenal M;Schrier M;Oude Vrielink JA;Agami R
通讯作者：
Agami R